Sirtuins are a class of enzymes known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases. Humans have seven sirtuins, Sirt1-7, that regulate a variety of biological processes, including aging, transcription, and metabolism. Therefore, small molecules that can regulate sirtuin activity can be used to treat several human diseases.
Several proteins (such as epidermal growth factor receptor 2 or HER2 for breast cancer treatment, BCR-ABL for chronic myeloid leukemia treatment) have been used as pharmacological targets for treating human cancers. However, due to the heterogeneity of cancer and the occurrence of drug resistance, there is an ongoing need for the identification of new protein targets and new pharmacological reagents for treating cancer.
Sirt2 is one of the seven members of the Sir2-family of NAD+-dependent deacetylases (or sirtuins) in humans. A general schematic of the process by which sirtuins catalyze NAD-dependent protein lysine deacetylation is shown in FIG. 1. Sirtuins have been conserved through evolution and have been implicated in a number of biological functions, perhaps foremost being the regulation of lifespan (e.g., Haigis, M. C., et al., Annu. Rev. Pathol. 5, 253-295, 2010; and Imai, S.-i., et al., Trends in Pharmacological Sciences 31, 212-220, 2010). Among the seven mammalian sirtuins, Sirt2 is the only cytosolic one (e.g., Michishita, E., et al., Mol. Biol. Cell 16, 4623-4635, 2005). Two cytosolic Sirt2 substrates have been identified and confirmed in cellular studies, α-tubulin and phosphoenolpyruvate carboxykinase (PEPCK) (e.g., North, B. J., et al., Mol. Cell 11, 437-444, 2003; Jiang, W., et al., Mol. Cell 43, 33-44, 2011). Sirt2 destabilizes microtubules by deacetylating α-tubulin Lys40. By deacetylating PEPCK and regulating PEPCK stability, Sirt2 also regulates gluconeogenesis.
The anti-cancer effects of small-molecule inhibitors of Sirt2 have been described, e.g., Heltweg, B., et al., Cancer Res. 66, 4368-4377, 2006; Zhang, Y., et al., Biochem. Biophys. Res. Commun. 386, 729-733, 2009. However, the known inhibitors generally have higher than optimal IC50 values against Sirt2, and also lack specificity against Sirt2. Moreover, attaining such specificity against Sirt2 could provide significant advantages for the treatment of particular types of cancer, such as breast cancer, and more particularly, triple negative breast cancer. Sirt2 has also been shown to be involved in neurodegenerative disease (e.g., Luthi-Carter, R., et al., Proc. Natl. Acad. Sci. USA, 107(17):7927-32, Apr. 27, 2010, and de Oliveira, R. M., et al., Front Pharmacol., 3:82, 2012). Thus, such inhibitors against Sirt2 could also provide an improved treatment of neurodegenerative disease.